This revised proposal is essentially a continuation of the studies initiated in 1990 on the molecular identification and characterization of genes related to hereditary eye diseases with a shift of focus toward congenital cataracts (CC). CC, clinically defined as opacities of the lens present at birth, account for roughly 10% of visual loss in humans. One-third of CC are estimated to be genetic in origin, with the heterogeneous autosomal dominant congenital cataract (ADCC) forms being the most prevalent. The proposed work on the study of ADCC is based on the assumption that this genetically heterogeneous and phenotypically variable group of disorders results from mutations in genes expressed in the fetal lens. The proposed approach can best be described as the candidate gene approach which utilizes tissue- or function-specific genes and their map position to identify disease-causing genes. To this end the candidate gene approach employs gene mapping, the identification of genetic variation, analysis of linkage in affected families and the subsequent characterization of mutations within candidate genes shown to cosegregate with ADCC loci. The genetic heterogeneity of ADCC makes it necessary to evaluate many cataract candidate genes in a large number of families. As only a limited number of cataract candidate genes are currently available, a major goal of the proposed work is the isolation of novel genes preferentially expressed in the fetal lens through the creation of bovine and human fetal lens cDNA libraries. We hypothesize that genes active during fetal lens development are responsible for many forms of ADCC, a disease which presents clinically at birth. Simultaneously, the pool of cataract candidate gene probes and the ADCC family database in the laboratory are being significantly expanded through the establishment of numerous national and international collaborations. Forty-five additional ADCC families have been ascertained. The ultimate identification of disease-causing mutations will enhance the understanding of the normal function of the candidate gene and its role in the pathogenesis of ADCC. This knowledge coupled with genetic linkage information, will improve the accuracy of genetic counseling and potentially permit more effective treatment of this costly visual disorder.